Gene Therapy for Homozygous Familial Hypercholesterolemia

Sponsor

First Affiliated Hospital Xi'an Jiaotong University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06125847

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an early phase 1, open-label, single-center, dose-escalation, pilot trial to evaluate the safety and efficacy of an intravenous infusion of NGGT006 in homozygous familial hypercholesterolemia (HoFH) patients with LDLR mutations. NGGT006 is an adeno-associated viral (AAV) serotype 8 vector carrying codon-optimized human LDLR gene, driving the expression of LDLR protein with normal function and promoting the clearance of low-density lipoprotein cholesterol (LDL-C).

Condition or Disease	Intervention/Treatment	Phase
Homozygous Familial Hypercholesterolemia	Genetic: NGGT006	Early Phase 1

Detailed Description

Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder of lipoprotein metabolism, characterized by extreme elevations in low-density lipoprotein cholesterol (LDL-C) and leading to early onset of severe coronary artery disease. This is an early phase 1, open-label, single-center, dose-escalation, pilot trial to evaluate the safety and efficacy of a single intravenous infusion of NGGT006 in HoFH patients with LDLR mutations. NGGT006 is an adeno-associated viral (AAV) serotype 8 vector carrying codon-optimized human LDLR gene, driving the expression of LDLR protein with normal function and promoting the clearance of low-density lipoprotein cholesterol (LDL-C). 3-12 subjects will be enrolled and divided into 3 groups according to the principle of dose escalation, respectively administered intravenous infusion of NGGT006 at low dose (7.5e12vg/kg), medium dose (1.5e13vg/kg) and high dose (3e13vg/kg). All subjects will undergo 52 weeks of treatment observation and further 260 weeks of long-term follow-up.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

12 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Clinical Study for the Safety and Efficacy of Intravenous Infusion of NGGT006 in Treatment of Homozygous Familial Hypercholesterolemia With LDLR Mutations

Anticipated Study Start Date :

Nov 1, 2023

Anticipated Primary Completion Date :

Nov 1, 2024

Anticipated Study Completion Date :

Nov 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NGGT006 3 doses of NGGT006 will be administered according to the principle of dose escalation	Genetic: NGGT006 Single intravenous infusion of NGGT006 at low dose (7.5e12vg/kg), medium dose (1.5e13vg/kg) and high dose (3e13vg/kg).

Arm

Intervention/Treatment

Experimental: NGGT006

3 doses of NGGT006 will be administered according to the principle of dose escalation

Genetic: NGGT006

Single intravenous infusion of NGGT006 at low dose (7.5e12vg/kg), medium dose (1.5e13vg/kg) and high dose (3e13vg/kg).

Outcome Measures

Primary Outcome Measures

Incidence of treatment-related adverse events (AE) and serious adverse events (SAE) [52 weeks]
Incidence of AE and SAE, as assessed by physical examinations, clinical laboratory parameters and adverse event reporting
Absolute change and percent change in LDL-C [52 weeks]
Change in LDL-C concentration from baseline to week 52

Secondary Outcome Measures

Absolute change and percent change in lipid parameters [52 weeks]
Change in lipid concentrations from baseline to week 52. Lipid parameters include: non-high density lipoprotein cholesterol (non-HDL-C); apolipoprotein B (apoB); total cholesterol (TC); HDL-C; triglycerides (TG); very low-density lipoprotein cholesterol (VLDL-C); lipoprotein(a) (Lp(a)); and apolipoprotein A-I (apo A-I)

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years to 35 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Voluntarily sign informed consent form;
Male or female, 12 ≤ age ≤ 35 years (first patient≥ 18 years), diagnosed as homozygous familial hypercholesterolemia with genetic confirmation of two mutant alleles of the LDL receptor (LDLR) gene;
Serum anti-AAV8 conjugate antibodies titer ≤ 1:80 and anti-AAV8 neutralizing antibodies titer ≤ 1:5;
Untreated LDL-C >10 mmol/L (180mg/ dL) or treated LDL-C ≥7 mmol/L (126 mg/ dL) together with cutaneous or tendon xanthoma before age 18 years;
Had been on stable medication for ≥30 days if receiving lipid-lowering therapy (or ≥60 days if receiving alirocumab or evolocumab) prior to screening and not scheduled for addition of new drugs or dose adjustments during the study;
Agreed to follow a low-fat diet and comply with all study procedures;
Agreed to maintain a similar exercise volume and intensity to baseline during the study period;
Agreed to maintain good lifestyle habits;
No history of alcohol abuse or alcohol dependence (diagnosed as F10 in ICD-10 code);
No sexual activity for 14 days prior to administration and negative serum pregnancy test in female participants;
Participants of childbearing potential agreed to use highly effective contraception for at least 365 days from administration of NGGT006;
No plan of stent implantation within 3 months.

Exclusion Criteria:

Positive for hepatitis B surface antigen, hepatitis C, human immunodeficiency virus (HIV) or syphilis test;
Clinically significant abnormalities in liver function test: alanine aminotransferase (ALT) >2 × upper limit of normal (ULN) and/or aspartate aminotransferase (AST) >2 × ULN;
Baseline blood pressure >160/100 mmHg (1 repeat measurement is allowed);
Uncontrolled myocardial infarction or heart failure, or had surgery plan within 1 year;
Diabetes diagnosed within 3 months or with poor control (HbA1c >9%);
Acute or chronic kidney failure;
Hemoglobin (Hb) < 120g/L (male), Hb < 110 (female);
Abnormal platelet counts or morphology;
History or laboratory tests suggestive of thrombosis;
Had contraindications to glucocorticoid (e.g., epilepsy, severe schizophrenia, active peptic ulcer);
Life expectancy less than 1 year;
With malignant tumors;
Liver fibrosis or liver cancer;
Previous gene therapy treatment;
Hypersensitivity to AAV or cortisone or immunosuppressants (sirolimus, rituximab, tacrolimus);
Participation in any other clinical trial within 3 months;
History of stent implantation within 1 month or myocardial infarction within 3 months;
Breastfeeding females;
Any other condition that may not be appropriate for the study in the opinion of the Investigator.